As HIV has evolved into a chronic disease, HIV-associated fat redistribution, or HIV lipodystrophy, has become a significant morbidity. Patients with HIV lipodystrophy have reduced growth hormone (GH) secretion, and GH therapy improves body composition in this population. Subcutaneous GH treatment does not mimic physiologic GH secretion, however, and consistently high levels of GH rather than pulsatile release may contribute to the side effects of GH therapy. Growth hormone releasing hormone (GHRH) is a novel therapy with potential to reduce visceral fat and improve markers of cardiovascular risk. GHRH augments endogenous pulsatile GH secretion and preserves negative feedback on somatotrophs by IGF-1. It may,therefore, be a more physiologically appropriate treatment for patients with HIV and fat redistribution. The first aim of this proposal is to compare the effects of GH and GHRH on GH pulsatility and insulin sensitivity. Twenty-five patients with HIV will receive either GH or GHRH daily for one week, followed by a one week observation period. At weeks 0, 1, and 2, patients will have frequent sampling to assess GH pulse dynamics, and insulin sensitivity will be measured using euglycemic hyperinsulinemic clamp. The hypothesis is that GHRH will augment GH pulse height and preserve pulse frequency, while GH will suppress GH pulsatility. Because of this difference, GH will cause greater insulin resistance than GHRH. The second aim is to investigate the long term effects of GHRH on body composition and cardiovascular health. Six months of GHRH therapy has been shown to reduce visceral fat by 15% in this population, but it is not known if this benefit will persist with longer duration of therapy. Further, the effect of GHRH on markers of cardiovascular risk is not well-characterized. In the proposed research, patients will be randomized to receive GHRH or placebo for 12 months. Endpoints will include changes in GH pulse dynamics, insulin sensitivity, intramyocellular lipid and hepatic fat using MR spectroscopy, carotid intimal medial thickness (CIMT), and inflammatory markers (adiponectin, C-reactive protein, tissue plasminogen activator, and plasminogen activator inhibitor-1). The hypothesis is that long-term GHRH therapy will improve body composition and cardiovascular health without adversely affecting insulin sensitivity. [unreadable] [unreadable] Public Health Relevance: This research will benefit public health in two important ways. First, GHRH is potentially an improved therapy for HIV-associated fat redistribution, and investigation of its use will benefit the growing number of patients with this condition. Second, understanding the mechanisms and metabolic consequences of this novel form of acquired lipodystrophy is relevant to treating obesity in the general population. [unreadable] [unreadable] [unreadable]